A controlled inflammatory response is beneficial when providing protection against infection;however dysregulated excessive inflammation contributes to disease pathogenesis in arthritis, cancer, cardiovascular disease, and a host of autoimmune conditions. This research project focuses on the role of the shed form of low density lipoprotein receptor related protein (sLRP-1) in inflammation. Our long-term goal is to understand the anti-inflammatory role of sLRP-1 in vivo and describe the mechanisms by which sLRP-1 is shed from the cell surface during inflammation. LRP-1 is a member of the LDL receptor gene family, which includes type I trans-membrane proteins that function in receptor-mediated endocytosis and cell signaling. Mature form of LRP-1 includes the 515 kDa a-chain and 85 kDa transmembrane p-chain. Shed form of LRP-1, which is detected in circulation, contains the a-chain (515 kDa subunit) and a 55 kDa fragment of the 3-chain. Recent evidence from our lab showed that in a rodent model of peripheral nerve injury, sLRP-1 expressed anti-inflammatory activity that did not result from competition with membrane-anchored LRP-1 for common ligands. In this research proposal we will test our major hypothesis that sLRP-1 exhibits anti- inflammatory biological activity in vivo and may represent a novel endogenous anti-inflammatory factor. In this application three specific aims are proposed. In Aim 1, we propose to elucidate the mechanism of LRP- 1 shedding and identify the protease responsible for this process. Aim 2 builds on preliminary data in which we have demonstrated that sLRP-1 accumulates in circulation during LPS-induced inflammation. We will continue these studies so we can understand how LPS challenge regulates accumulation of sLRP-1 in plasma in wild-type mice. Studies will also be conducted to test whether sLRP-1 in circulation is primarily blood cells originated. In Aim 3, we will determine whether endogenously-produced and exogenously- administered sLRP-1 regulates development of inflammation in response to LPS. Understanding the physiological significance of sLRP-1 accumulation in blood during inflammation and sLRP-1 anti- inflammatory potential are the critical objectives. Additionally, we will perform pharmacologic characterization of sLRP-1 in circulation in vivo. Studies will be made to determine parameters such as plasma half-life, distribution half-life, and organ biodistribution of sLRP-1 that are essential for the development of any pharmaceutical. This project will contribute to our understanding of the pathophysiology of inflammation and provide critical information regarding how sLRP-1 may represent a novel endogenous anti-inflammatory factor.